Lower dosage strength imiquimod formulations and shorter dosing regimens for treating actinic keratoses

Abstract

Pharmaceutical formulations and methods for the topical or transdermal delivery of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, i.e., imiquimod, to treat actinic keratosis with short durations of therapy, than currently prescribed for the commercially available Aldara® 5% imiquimod cream, as now approved by the U.S. Food & Drug Administration (“FDA”), are disclosed and described. More specifically, lower dosage strength imiquimod formulations to deliver an efficacious dose of imiquimod for treating actinic keratosis with an acceptable safety profile and dosing regimens that are short and more convenient for patient use than the dosing regimen currently approved by the U.S. Food & Drug Administration (“FDA”) for Aldara® 5% imiquimod cream to treat actinic keratosis are also disclosed and described.

1 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 6 weeks to achieve at least partial clearance of AK lesions.   
     
     
         2 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 4 weeks to achieve at least partial clearance of AK lesions.   
     
     
         3 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 3 weeks to achieve at least partial clearance of AK lesions.   
     
     
         4 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 2 weeks to achieve at least partial clearance of AK lesions.   
     
     
         5 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to three weeks to complete a first cycle,   resting for up to three weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for up to a three weeks to complete a second cycle, to achieve at least partial clearance of AK lesions.   
     
     
         6 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for three weeks to complete a first cycle,   resting for up to three weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for three weeks to complete a second cycle, to achieve at least partial clearance of AK lesions.   
     
     
         7 . A method of  claim 1 , wherein the imiquimod is applied in accordance with a 3×3×3 treatment regimen. 
     
     
         8 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to two weeks to complete a first cycle,   resting for up to two weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for up to two weeks to complete a second cycle, to achieve at least partial clearance of AK lesions.   
     
     
         9 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for two weeks to complete a first cycle,   resting for up to two weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for two weeks to complete a second cycle, to achieve at least partial clearance of AK lesions.   
     
     
         10 . A method of  claim 2 , wherein the imiquimod is applied in accordance with a 2×2×2 treatment regimen. 
     
     
         11 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 6 weeks to achieve at least complete clearance of AK lesions.   
     
     
         12 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 4 weeks to achieve at least complete clearance of AK lesions.   
     
     
         13 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 3 weeks to achieve at least complete clearance of AK lesions.   
     
     
         14 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 2 weeks to achieve at least complete clearance of AK lesions.   
     
     
         15 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to three weeks to complete a first cycle,   resting for up to three weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for up to a three weeks to complete a second cycle, to achieve at least complete clearance of AK lesions.   
     
     
         16 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for three weeks to complete a first cycle,   resting for up to three weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for three weeks to complete a second cycle, to achieve at least complete clearance of AK lesions.   
     
     
         17 . A method of  claim 15 , wherein the imiquimod is applied in accordance with a 3×3×3 treatment regimen. 
     
     
         18 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to two weeks to complete a first cycle,   resting for up to two weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for up to two weeks to complete a second cycle, to achieve at least complete clearance of AK lesions.   
     
     
         19 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for two weeks to complete a first cycle,   resting for up to two weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for two weeks to complete a second cycle, to achieve at least complete clearance of AK lesions.   
     
     
         20 . A method of  claim 18 , wherein the imiquimod is applied in accordance with a 2×2×2 treatment regimen. 
     
     
         21 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 6 weeks to achieve a reduction in the number clearance of AK lesions.   
     
     
         22 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 4 weeks to achieve a reduction in the number clearance of AK lesions.   
     
     
         23 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 3 weeks to achieve a reduction in the number clearance of AK lesions.   
     
     
         24 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to 2 weeks to achieve a reduction in the number clearance of AK lesions.   
     
     
         25 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to three weeks to complete a first cycle,   resting for up to three weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for up to a three weeks to complete a second cycle, to achieve a reduction in the number clearance of AK lesions.   
     
     
         26 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for three weeks to complete a first cycle,   resting for up to three weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for three weeks to complete a second cycle, to achieve a reduction in the number clearance of AK lesions.   
     
     
         27 . A method of  claim 25 , wherein the imiquimod is applied in accordance with a 3×3×3 treatment regimen. 
     
     
         28 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for up to two weeks to complete a first cycle,   resting for up to two weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for up to two weeks to complete a second cycle, to achieve a reduction in the number clearance of AK lesions.   
     
     
         29 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying an effective amount of imiquimod to a treatment area once a day for two weeks to complete a first cycle,   resting for up to two weeks, wherein no imiquimod is applied to the subject,   applying an effective amount of imiquimod to the treatment area once a day for two weeks to complete a second cycle, to achieve a reduction in the number clearance of AK lesions.   
     
     
         30 . A method of  claim 28 , wherein the imiquimod is applied in accordance with a 2×2×2 treatment regimen. 
     
     
         31 . A method of anyone of  claims 1 - 30 , wherein the effective amount of imiquimod is applied from a lower dosage strength imiquimod formulation. 
     
     
         32 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation comprises imiquimod and a fatty acid. 
     
     
         33 . A method of  claim 32 , wherein the fatty acid is selected from a group consisting of stearic acid, palmitic acid, unrefined oleic acid, linoleic acid, isostearic acid and super refined oleic acid. 
     
     
         34 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1% and about 425% w/w. 
     
     
         35 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 425%. 
     
     
         36 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. 
     
     
         37 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. 
     
     
         38 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 2.5%. 
     
     
         39 . A method of  claim 31 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75% imiquimod. 
     
     
         40 . A method of  claim 32 , wherein the fatty acid is unrefined oleic acid. 
     
     
         41 . A method of  claim 32 , wherein the fatty acid is refined oleic acid. 
     
     
         42 . A method of  claim 32 , wherein the fatty acid is isostearic acid. 
     
     
         43 . A method of  claim 32 , wherein the lower dosage strength imiquimod formulation is selected from a group of formulations listed in Table 9. 
     
     
         44 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying a lower dosage strength imiquimod formulation to a treatment area once a day for each day during a short duration of therapy to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         45 . A method of treating a subject diagnosed with actinic keratosis of  claim 44 , wherein the lower dosage strength imiquimod formulation is selected from the group consisting of lower dosage strength imiquimod formulations set forth in Example 23. 
     
     
         46 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying a lower dosage strength imiquimod formulation comprising about 3.75% imiquimod by weight to a treatment area once a day for each day in accordance, with a short duration of therapy to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         47 . A method of treating a subject diagnosed with actinic keratosis of  claim 46 , wherein the 3.75% imiquimod formulation is selected from the group consisting of the 3.75% imiquimod formulations set forth in Example 23. 
     
     
         48 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying a lower dosage strength imiquimod formulation comprising about 2.5% imiquimod by weight to a treatment area once a day for each day in accordance with a short duration of therapy to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         49 . A method of treating a subject diagnosed with actinic keratosis of  claim 48 , wherein the 2.5% imiquimod formulation is selected from the group consisting of 2.5% imiquimod formulations set forth in Example 23. 
     
     
         50 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 3.75% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises a fatty acid, to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         51 . A method of treating a subject diagnosed with actinic keratosis of  claim 50 , wherein the 3.75% imiquimod formulation is selected from the group consisting of 3.75% imiquimod formulations set forth in Example 23. 
     
     
         52 . A method of treating a subject diagnosed with actinic keratosis of  claim 50 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, unrefined oleic acid, super refined oleic acid, stearic acid, isostearic acid and mixtures thereof. 
     
     
         53 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 2.5% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises a fatty acid, to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         54 . A method of treating a subject diagnosed with actinic keratosis of  claim 53 , wherein the 2.5% imiquimod formulation is selected from the group consisting of the 2.5% imiquimod formulations set forth in Example 23. 
     
     
         55 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 3.75% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises isostearic acid, to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         56 . A method of treating a subject diagnosed with actinic keratosis of  claim 55 , wherein the 3.75% imiquimod formulation is selected from the group consisting of the 3.75% imiquimod formulations set forth in Example 23. 
     
     
         57 . A method of treating a subject diagnosed with actinic keratosis, said method comprises
 applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 2.5% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises isostearic acid, to deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis.   
     
     
         58 . A method of treating a subject diagnosed with actinic keratosis of  claim 51 , wherein the 2.5% imiquimod formulation is selected from the group consisting of the 2.5% imiquimod formulations set forth in Example 23. 
     
     
         59 . An imiquimod formulation for treating actinic keratosis, said imiquimod formulation comprising:
 a lower dosage strength of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod), and   a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises a fatty acid, for application to a treatment area once a day for a short duration of therapy to topically or transdermally deliver an effective amount of imiquimod to the treatment area to treat actinic keratosis   
     
     
         60 . An imiquimod formulation of  claim 59 , wherein the said application of said imiquimod formulation is without inducing significant local skin reactions or irritation in the treatment area or treatment limiting adverse events which could result in premature therapy termination or significant voluntary rest periods of several days that are generally associated with higher concentrations of imiquimod therapy. 
     
     
         61 . An imiquimod formulation of claim NM, wherein the lower dosage strength imiquimod formulation is selected from a group of lower dosage strength of imiquimod formulations set forth in Table 9. 
     
     
         62 . An imiquimod formulation of  claim 59  wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, stearic acid, isostearic acid, unrefined oleic acid, super refined oleic acid and mixtures thereof. 
     
     
         63 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength of imiquimod is about 3.75% 
     
     
         64 . An imiquimod formulation of  claim 63  wherein the 3.75% imiquimod formulation is selected from a group consisting of the 3.75% imiquimod formulations in Example 23. 
     
     
         65 . An imiquimod formulation of  claim 63 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, stearic acid, isostearic acid, unrefined oleic acid, super refined oleic acid and mixtures thereof. 
     
     
         66 . An imiquimod formulation of  claim 63 , wherein the fatty acid is isostearic acid. 
     
     
         67 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength of imiquimod is about 2.5% 
     
     
         68 . An imiquimod formulation of  claim 67 , wherein the 2.5% imiquimod formulation is selected from a group consisting of the 2.5% imiquimod formulations in Example 23. 
     
     
         69 . An imiquimod formulation of  claim 67 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, stearic acid, isostearic acid, unrefined oleic acid, super refined oleic acid and mixtures thereof. 
     
     
         70 . An imiquimod formulation of  claim 67 , wherein the fatty acid is isostearic acid. 
     
     
         71 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1.0% and about 425%. 
     
     
         72 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 40% and 4.25%. 
     
     
         73 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. 
     
     
         74 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. 
     
     
         75 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 2.5%. 
     
     
         76 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75% imiquimod. 
     
     
         77 . An imiquimod formulation of  claim 59 , wherein the fatty acid is present in an amount of between about 5% and 30% by weight. 
     
     
         78 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation has dose proportionate release rates as to both the release fates of the imiquimod and the total amount of imiquimod released, relative to the Aldara® 5% imiquimod cream. 
     
     
         79 . An imiquimod formulation of  claim 76 , wherein the fatty acid is isostearic acid. 
     
     
         80 . An imiquimod formulation of  claim 78 , wherein the imiquimod is present in an amount of about 3.75% by weight. 
     
     
         81 . An imiquimod formulation of  claim 78 , wherein the imiquimod is present in an amount of about 2.5% by weight. 
     
     
         82 . An imiquimod formulation of anyone of  claims 59 - 81 , wherein the lower dosage strength imiquimod formulation is bioequivalent. 
     
     
         83 . An imiquimod formulation of anyone of  claims 59 - 81 , wherein the lower dosage strength imiquimod formulation is therapeutically equivalent. 
     
     
         84 . An imiquimod formulation of anyone of  claims 59 - 81 , wherein the lower dosage strength imiquimod formulation is pharmaceutically equivalent. 
     
     
         85 . An imiquimod formulation of anyone of  claims 59 - 81 , wherein the lower dosage strength imiquimod formulation is interchangeable. 
     
     
         86 . An imiquimod formulation of anyone of  claims 59 - 81  wherein the lower dosage strength imiquimod formulation remains free of degradation products when stored at about 25° C./60% RH, about 30° C./65% RH and about 40° C./75% RH over about one, about two, about three and about six months and when analyzed at about 318 nm wavelength. 
     
     
         87 . An imiquimod formulation of anyone of  claims 59 - 81 , wherein the lower dosage strength imiquimod formulation has an in-vivo serum profile selected from the group consisting of:
 (a) a Day 21 T max  of from about 4 hours to about 16 hours and preferably a mean T max  of about 7.4 hours with a standard deviation (“SD”) of about 3.5, a median T max  of about 9 hours and a geometric mean T max  of about 6.6 hours and a coefficient of variation (“CV”) of about 48%;   (b) a Day 21 C max  of from about 0.07 to about 0.6 ng/ml and preferably a mean C max  of about 0.3 ng/ml with a standard deviation of about 0.16, a median C max  of about 0.35 and a geometric mean C max  of about 0.27 ng/ml and a coefficient of variation of about 49%;   (c) a Day 21 T 1/2  of from about 9.7 to about 84 hours and preferably a mean T 1/2  of about 29.3 hours with a standard deviation of about 17, a median T 1/2  of about 25.6 hours and a geometric mean T 1/2  of about 26 hours and a coefficient of variation of about 58%;   (d) a Day 21 AUC 0-24  of from about 1.1 to about 12 ng·hr/ml and preferably a mean AUC 0-24  of about 6 ng·hr/ml with a standard deviation of about 3, a median AUC 0-24  of about 7 ng·hr/ml and a geometric mean AUC 0-24  of about 5 ng·hr/ml and a coefficient of variation of about 52%;   (e) a Day 21 λz of from about 0.008 hr −1  (to about 0.07 hr −1  and preferably a mean λz of about 0.03 hr −1  with a standard deviation of about 0.01, a median λz of about 25.6 hr −1  and a geometric mean λz of about 0.03 hr −1  and a coefficient of variation of about 49%;   (f) a Day 21 C min  of from about 0.06 to about 0.4 and preferably a mean C min  of about 0.20 with an SD of about 0.11, a median C min , of about 0.19 and a geometric mean C min  of about 0.17 and a coefficient of variation of about 55%;   (g) at Day 14/7 (a ratio of the trough concentration at Day 14 over the trough concentration at Day 7), a trough concentration geometric mean ratio of about 1.09 with a 90% confidence interval (“CI”) within a range of between about 0.8 and about 1.5;   (h) at Day 21/14 (a ratio of the trough concentration at Day 21 over the trough concentration at Day 14), a trough concentration geometric mean ratio of about 1.33 with a 90% confidence interval (“CI”) within a range of between about 0.9 and about 1.9;   (i) at Day 22/21 (a ratio of the trough concentration at Day 22 over the trough concentration at Day 21) a trough concentration geometric mean ratio of about 0.93 with a 90% confidence interval (“CI”) within a range of between about 0.6 and about 1.3;   (j) a mean peak imiquimod serum concentration of about 0.323 ng/ml at Day 21;   (k) a Day 21 RAUC of from about 1 to about 7 and preferably a mean RAUC of about 4 with a standard deviation of about 2, a median RAUC of about 3.5 and a geometric mean RAUC of about 3.3 and a coefficient of variation of about 56%;   (l) a Day 21 RC max  of from about 0.5 to about 5 and preferably a mean RC max  of about 3 with a standard deviation of about 1.5, a median RC max  of about 2.7 and a geometric mean RC max  of about 2.4 and a coefficient of variation of about 54%;   (m) a Day 21 Lλz eff  of from about 0.006 hr −1  to about 0.08 hr −1  and preferably a mean Lλz eff  of about 0.02 hr −1  with a standard deviation of about 0.02, a median Lλz eff  of about 0.01 hr −1  and a geometric mean Lλz eff  of about 0.16 hr −1  and a coefficient of variation of about 97%; and   (n) a Day 21 T 1/2   eff  of from about 8 hr to about 110 hr and preferably a mean T 1/2   eff  of about 55 hr with a standard deviation of about 36, a median T 1/2   eff  of about 50 hr and a geometric mean T 1/2   eff  of about 42 hr −1  and a coefficient of variation of about 66%.   
     
     
         88 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation achieves a steady state by about week 2, e.g., between about day 8 and day 14, when approximately 500 mg or less of said formulation is applied daily for 21 days to a treatment area of about 200 cm 2  on the face or balding scalp of a subject. 
     
     
         89 . An imiquimod formulation of  claim 59 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75%. 
     
     
         90 . A camel back pattern of local skin reaction sum score, wherein said camel back pattern is generated from the treatment of acynic keratosis with an effective amount of imiquimod delivered from a lower dosage strength imiquimod formulation when applied once a day in accordance with a 2×2×2 treatment regimen, 
     
     
         91 . A camel back pattern of local skin reactions of  claim 90 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1% and about 4.25% w/w. 
     
     
         92 . A camel back pattern of local skin reactions of  claim 90 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 4.25%. 
     
     
         93 . A camel back pattern of local skin reactions of  claim 90 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. 
     
     
         94 . A camel back pattern of local skin reactions of  claim 90 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. 
     
     
         95 . A camel back pattern of local skin reactions of  claim 90 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 2.5%. 
     
     
         96 . A camel back pattern of local skin reactions of  claim 90 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75% imiquimod. 
     
     
         97 . A camel back pattern of mean local skin reaction erythema score, wherein said camel back pattern is generated from the treatment of acynic keratosis with an effective amount of imiquimod delivered from a lower dosage strength imiquimod formulation when applied once a day in accordance with a 2×2×2 treatment regimen, 
     
     
         98 . A camel back pattern of local skin reactions of  claim 97 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1% and about 4.25% w/w. 
     
     
         99 . A camel back pattern of local skin reactions of  claim 97 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3:75%, 4.0% and 4.25%. 
     
     
         100 . A camel back pattern of local skin reactions of  claim 97 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. 
     
     
         101 . A camel back pattern of local skin reactions of  claim 97 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. 
     
     
         102 . A camel back pattern of local skin reactions of  claim 97 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 2.5%. 
     
     
         103 . A camel back pattern of local skin reactions of  claim 97 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75% imiquimod.